Biomedical Engineering Reference
In-Depth Information
heparin allows for simultaneous formation of AT-heparin and thrombin-heparin complexes, which
are mutually repulsive.
30
ATH removes this roadblock by making simultaneous occurrence of hepa-
rin complexes with AT and thrombin impossible. Other features stemming from effective cloak-
ing of AT surface areas may give ATH superior pharmacodynamics. Stable coverage of the AT
polypeptide by heparin polysaccharide should sterically hinder proteases and some glycosidases.
Reduction in degradation by this means elongates the circulatory half-life by preventing its conver-
sion to products that are readily eliminated by the liver or spleen. In a similar manner, blockage
of heparin-epitope recognition by the conjugated AT could make for a reduced immunological
response. Therefore, if a smaller length of the heparin is available for external interactions, ATH
may have a lowered induction of thrombocytopenic antibody generation akin to that of a LMWH.
183
In a similar sense, ATH heparin chains may mirror the LMWH's lack of capacity to trigger bone
resorption in osteoporosis.
209
Finally, the major hemorrhagic side effects of heparin usage may be
moderated if ATH remains in close contact. Platelet binding of ATH could be limited if the AT
protein suffi ciently interferes with adsorption to the PF4 receptor.
210,211
Alternatively, if ATH binds
to PF4, factors responsible for aggregation may be muted by the presence of the AT protein. Overall,
almost every category of heparin defi ciency seems to be an object for improvement with a simple
bonding to the GAG's natural serpin target. If these projections are true, ATH should lend itself to
advancements in a number of clinical indications.
The limitations of heparins, to date, that have obstructed a number of its applications may be reach-
able with some of the enhanced structure and functions intrinsic in ATH. Increased rate of thrombin
inhibition by ATH over UFH would signifi cantly improve prophylactic treatment of prothrombotic
conditions. If ATH more rapidly inhibits thrombin, then the ultralow concentrations of thrombin
formed during the initiation stage of coagulation would not have the opportunity to cause the burst
of coagulant activity from feedback activation of FV, FVIII, and FXI. In addition to the dampening
of thrombin's activating function, a prolonged half-life of ATH over heparin means that prophy-
laxis by the conjugate may only require a single bolus injection. Thus, hospital and home care for
ATH may be more facile and monitoring may be unnecessary if bleeding risk is lowered by a lack
of platelet effects. The possibility that ATH can effectively inhibit clot-bound thrombin gives it a
strong endorsement as an antithrombotic treatment agent. Thus, neutralization of fi brin clot-bound
thrombin by ATH would be a major breakthrough, given that clot extension is believed to origi-
nate from fl uid phase activation of coagulation by factors, such as thrombin, residing on the clot
surface.
42-44
If the anticoagulant potency of ATH is as avid as suggested, the plasma concentrations
required for successful treatment will be relatively low, which bodes well for reduction from the
levels of drug that can induce bleeding. An increased half-life due to reduced renal loss adds to
the lower estimate of ATH that should be necessary for proper medication and lowered hemorrhagic
risk. The diffi culty for ATH to pass through tissue because of size constraint leads to another option
not available with heparin treatments. Size restriction of ATH could allow for sequestration within
various vascular compartments. Therefore, ATH could be used to anticoagulate or pacify a region of
interest without causing undesired anticoagulant effects in other spaces. One useful application of this
property occurs in the respiratory distress syndrome (RDS) exhibited in premature infants. Under-
development of the lung in premature neonates, as well as acute or chronic lung damage in adults,
causes permeability of plasma proteins into the airway.
212-214
Proteins of the coagulation cascade
are eventually activated to deposit fi brin, a hallmark of RDS that complicates respiration,
215,216
increasing the occurrence and severity of long-term and chronic bronchopulmonary displasia.
217-223
Therefore, a pulmonary anticoagulant treatment could arrest much of the damage and fi brotic
disease associated with prematurity. Previous work with UFH has shown that instead of being
maintained within the lung, heparin is readily secreted from the alveoli into the systemic circula-
tion.
40
Even if UFH could be retained in the airspace, it is unclear if suffi cient amounts of AT are
available for UFH to act. ATH may solve this problem. Migration of ATH complex across the lung
membrane would be slow if at all, allowing the agent to inhibit coagulation in a concentrated state
within the surfactant fi lm on the epithelium. This application may be one of the more outstanding
